Abstract：
Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory mRNAs. Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated mTORC1 pathway and facilitated the autoimmune trait in D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune function and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses.
摘要：
Regnase-1是一种RNase，通过使炎症mRNA不稳定，在负调节免疫应答中起关键作用。Regnase-1的功能紊乱可能是各种炎症性疾病的主要原因，包括组织损伤和免疫细胞浸润到器官中。这项研究集中于Regnase-1的RNase活性在发展炎症性疾病中的作用。我们已经构建了在Regnase-1RNase结构域的催化中心具有单点突变的小鼠，缺乏核酸内切酶活性。D141N突变小鼠表现出全身性炎症，免疫细胞浸润到各种器官和进行性发展的肺肉芽肿。CD4+T细胞,主要受这种突变的影响，在D141N突变中上调mTORC1通路并促进自身免疫性状。此外，丝氨酸/苏氨酸激酶Pim2参与了该突变中的肺部炎症。抑制Pim2激酶活性改善肉芽肿性炎症，免疫细胞在肺部的浸润和增殖。此外,Pim2抑制降低了CD4+T细胞上粘附分子的表达,提示Pim2在促进白细胞粘附和迁移到发炎组织中的作用。我们的发现为Regnase-1RNase活性在控制免疫功能中的作用提供了新的见解，并强调了靶向Pim2调节异常免疫反应的治疗相关性。
